Understanding and Improving Recovery From COVID-19
Authors: Aluko A. Hope
Journal: Annals of Internal Medicine (2022)

EditorialsJuly 2022Understanding and Improving Recovery From COVID-19FREEAluko A. Hope, MD, MSCEAluko A. Hope, MD, MSCEOregon Health & Science University, Portland, OregonAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M22-1492 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail The COVID-19 pandemic emerged at a time when we had won our way to a hilltop where many diseases are treatable. Improved treatment means that our health systems need to care for an increasing number of survivors of all types, including cancer survivors, older adults living with multiple comorbid conditions, and survivors of severe critical illnesses struggling to reintegrate into society (1). Humbled and cast down as we were by the tragedy of the worst of the COVID-19 pandemic, there was reassurance in the fact that many patients with SARS-CoV-2 infection were asymptomatic or had mild acute illness. We were unprepared for the onslaught of survivors of acute SARS-CoV-2 infection with persistent symptoms long after acute illness. Many of these patients present requesting diagnoses, expecting treatment, and worrying about their future lives in the shadow of COVID-19. Too often, these patients suffer the injustices of not being believed, being misdiagnosed as having anxiety disorder, or having their symptoms misattributed to pandemic stress (2).Research from studies using questionnaire data and analysis of electronic medical records has largely verified the sobering reality that a significant proportion of people with SARS-CoV-2 infection have persistent symptoms months after the acute illness (3–5). Across multiple studies, the most common symptoms include fatigue, cognitive changes, difficulty breathing, changes in smell or taste, and headache (6). The World Health Organization defines post-COVID syndrome as a cluster of overlapping signs or symptoms across multiple systems that develop during or after probable or confirmed SARS-CoV-2 infection and continue for more than 12 weeks after the infection (7). Few studies have included both participants with and participants without a history of SARS-CoV-2 infection.In their article, Sneller and colleagues provide a valuable contribution to our growing understanding of postacute sequelae of SARS-CoV-2 infection (PASC) by reporting the results of their baseline clinical and immunologic evaluations in 309 participants enrolled during the first year of an ongoing longitudinal study (8). This report includes 2 groups: 189 adults with a history of laboratory-confirmed SARS-CoV-2 infection (the mean time from symptom onset to enrollment was 162 days, and all participants were without worsening respiratory symptoms or fever within 7 days of enrollment), and 120 control participants with no history of a COVID-19–like illness or antibodies to SARS-CoV-2. For the group with previous SARS-CoV-2 infection, PASC was defined as any symptom or medical condition that began or worsened after the COVID-19 illness and was still present at the time of enrollment. All participants underwent an extensive evaluation that included review of their medical history, a questionnaire about the presence or absence of 17 symptoms, neurocognitive assessment, brief screening for depression and anxiety, and measurement of health-related quality of life using the Short Form-36 Health Survey. The participants also provided blood samples that the investigators used to compare the level of soluble markers of inflammation and high-dimensional T-cell phenotyping between the 2 groups.The study results will be unsurprising to clinicians who have been seeing a high volume of patients with PASC. First, participants with PASC reported more symptoms and worse physical and mental health status than COVID-19 survivors without PASC or control participants. Patients with PASC reported a median of 2 (IQR, 1 to 4) symptoms, with the most common being fatigue, dyspnea, changes in smell, cognitive changes, and sleep changes. Second, the investigators found few differences between COVID-19 survivors and control participants in objective tests, such as physical examination, neurocognitive assessment, and plasma inflammatory biomarkers. Importantly, they found no differences in the levels of immunologic markers that might indicate a potential immunologic mechanism for PASC.This is a small study of a group of highly motivated participants, and these findings should not lead to changes in clinical care. However, the study's strengths include that the extensive evaluations performed as part of the study protocol mirror the often exhaustive and expensive evaluations that many patients with PASC get when they seek care. After these patients endure these evaluations, they are often told that everything is normal and nothing is wrong, implying that their subjective reports are less credible than the objective findings. Unfortunately, this study did not attempt to measure an important symptom complex that many believe is the hallmark of PASC: postexertional symptom exacerbation, or postexertional malaise (PEM) (4, 9). This refers to worsening of the patient's fatigue, cognitive changes, and other symptoms after physical, cognitive, social, or emotional exertion. Patients report that the worsening is often delayed from the onset of the trigger and out of proportion to the degree of exertion. Practically, acknowledging the importance of PEM means that detailed subjective and objective assessments need to account for the fact that patients' symptoms and performance may change dramatically depending on whether they are in a restful or stressful state. In addition, assessment of PEM needs to consider stressful states in the context of a patient's pre–COVID-19 level of function and fitness across multiple health domains. Future studies need to better capture these issues.Although the investigators aimed to enroll post–COVID-19 participants with a wide spectrum of initial disease severity and without regard for the presence or absence of PASC, the nature of their recruitment process may have led to overrepresentation of patients with higher levels of physical function who were nevertheless worried about persistent symptoms. Importantly, the control participants were not matched on age or gender, and the investigators conducting the physical examinations were not blinded to study group. Although their definition of PASC has face validity, the investigators did not consider how other more restrictive definitions would have affected their findings. Their approach to identifying comorbid conditions, such as anxiety, in the study sample likely overrepresented this diagnosis in patients with PASC given that central or peripheral autonomic impairment is a common feature of many postviral fatigue syndromes and is often misdiagnosed as an anxiety syndrome. Because most of the study enrollment occurred before the advent of COVID-19 vaccines, these findings may not be generalizable to a population of fully vaccinated adults.As we emerge from the hell of the COVID-19 pandemic, it is time to insist on painstaking study and care of survivors of COVID-19. Without a fuller understanding of pathophysiology and disease course, we must not allow normal objective tests to negate our patients' subjective experiences. We need to explore whether real-world measurements during both restful and stressful conditions offer insight into the mechanisms of PASC. While we gather evidence, our patients deserve personalized care pathways that acknowledge the many biopsychosocial factors involved in illness recovery.References1. Prescott HC, Iwashyna TJ, Blackwood B, et al. Understanding and enhancing sepsis survivorship. Priorities for research and practice. Am J Respir Crit Care Med. 2019;200:972-81. [PMID: 31161771] doi:10.1164/rccm.201812-2383CP CrossrefMedlineGoogle Scholar2. Hope AA, Munro CL. Testimonies from the pandemic shore. Am J Crit Care. 2021;30:88-90. [PMID: 33644796] doi:10.4037/ajcc2021989 CrossrefMedlineGoogle Scholar3. Nehme M, Braillard O, Chappuis F, et al; CoviCare Study Team. Prevalence of symptoms more than seven months after diagnosis of symptomatic COVID-19 in an outpatient setting. Ann Intern Med. 2021;174:1252-60. [PMID: 34224254] doi:10.7326/M21-0878 LinkGoogle Scholar4. Davis HE, Assaf GS, McCorkell L, et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021;38:101019. [PMID: 34308300] doi:10.1016/j.eclinm.2021.101019 CrossrefMedlineGoogle Scholar5. Sudre CH, Murray B, Varsavsky T, et al. Attributes and predictors of long COVID. Nat Med. 2021;27:626-31. [PMID: 33692530] doi:10.1038/s41591-021-01292-y CrossrefMedlineGoogle Scholar6. Lopez-Leon S, Wegman-Ostrosky T, Perelman C, et al. More than 50 long-term effects of COVID-19: a systematic review and meta-analysis. Sci Rep. 2021;11:16144. [PMID: 34373540] doi:10.1038/s41598-021-95565-8 CrossrefMedlineGoogle Scholar7. World Health Organization. A clinical case definition of post COVID-19 condition by a Delphi consensus, 6 October 2021. Accessed at www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1 on 12 May 2022. Google Scholar8. Sneller MC, Liang CJ, Marques AR, et al. A longitudinal study of COVID-19 sequelae and immunity: baseline findings. Ann Intern Med. 2022;175:969-79. doi:10.7326/M21-4905 LinkGoogle Scholar9. Singh I, Joseph P, Heerdt PM, et al. Persistent exertional intolerance after COVID-19: insights from invasive cardiopulmonary exercise testing. Chest. 2022;161:54-63. [PMID: 34389297] doi:10.1016/j.chest.2021.08.010 CrossrefMedlineGoogle Scholar Comments0 CommentsSign In to Submit A Comment Gregory John Patton, MDTeam Health24 May 2022 Post COVID Syndrome As a survivor of severe COVID, I think they should consider muscle biopsy for those with persistent myalgias and look at mitochondrial dysfunction in those with chronic fatigue. Christa Hines, LCSWPsychotherapist in Private Practice2 July 2022 The Misunderstood Autonomic Dysfunction of Long Covid is eroding pt. care Dr. Hope, I am extremely grateful that you are broadening the lens of Dr. Sneller's painfully narrow study. As a Neuropsychotherapist and person with Long Covid since April of 2020, I know personally and professionally that autonomic dysfunction is not easily identified with any of Dr. Sneller's tests and is prominant in patient's with Long Covid. In addition to being life changing and disabling on multiple levels, it is not easily identified and way too often misidentified as "anxiety" when the body is stuck in a survival state of sympathetic overdrive. Dr. Hope, I apprecaite your voice as a clinical representative of those of us still suffering and left without clear testing or treatment. Author, Article, and Disclosure InformationAuthors: Aluko A. Hope, MD, MSCEAffiliations: Oregon Health & Science University, Portland, OregonDisclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-1492.Corresponding Author: Aluko A. Hope, MD, MSCE, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, UHN67, Portland, OR 97239; e-mail, [email protected]edu.This article was published at Annals.org on 24 May 2022. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoA Longitudinal Study of COVID-19 Sequelae and Immunity: Baseline Findings Michael C. Sneller , C. Jason Liang , Adriana R. Marques , Joyce Y. Chung , Sujata M. Shanbhag , Joseph R. Fontana , Haniya Raza , Onyi Okeke , Robin L. Dewar , Bryan P. Higgins , Katie Tolstenko , Richard W. Kwan , Kathleen R. Gittens , Catherine A. Seamon , Genevieve McCormack , Jacob S. Shaw , Grace M. Okpali , Melissa Law , Krittin Trihemasava , Brooke D. Kennedy , Victoria Shi , J. Shawn Justement , Clarisa M. Buckner , Jana Blazkova , Susan Moir , Tae-Wook Chun , and H. 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